#325 - 📑 Journal Club - The Complete Episode from June 29th 2025

Hello friends 👋

In this week’s Journal Club, Ben and Daphna unpack a series of recent studies exploring outcomes in neonatology—from long-term mortality after severe neonatal morbidity to short-term feeding strategies in preterm infants.

They open with a large population-based Swedish study showing that infants who experience severe neonatal morbidities face elevated mortality risks well into adolescence—especially those with neurological complications. The discussion highlights how early-life diagnoses carry weight far beyond the NICU, and how long-term support systems may not be fully equipped to manage that risk.

Next, the hosts examine a small German crossover trial on prone positioning, revealing that even simple changes in posture may cut hypoxemic episodes in half. They follow this with a randomized trial comparing dopamine and norepinephrine for neonatal septic shock, a data-heavy look at the nuanced physiology behind first-line interventions.

The episode rounds out with studies on cold milk for feeding dysphagia, late-onset sepsis risk with hydrocortisone, the impact of tele-neonatology on cooling time in HIE, and a new meta-analysis on kangaroo care’s role in reducing infection.

It’s a pragmatic, fast-paced overview of recent literature shaping how we care for vulnerable newborns.

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The articles covered on today’s episode of the podcast can be found here 👇

Severe Neonatal Morbidity and All-Cause and Cause-Specific Mortality Through Infancy and Late Adolescence.

Graham H, Johansson K, Persson M, Norman M, Razaz N.JAMA Pediatr. 2025 Jun 10:e251873. doi: 10.1001/jamapediatrics.2025.1873. Online ahead of print.PMID: 40493844

Prone Positioning Was Associated With Less Hypoxemic Events and Improved Feeding Tolerance in Preterm Infants.

Bohnhorst B, Lutz E, Pirr S, Peter C, Böhne C.Acta Paediatr. 2025 May 26. doi: 10.1111/apa.70153. Online ahead of print.PMID: 40418109

Prophylactic hydrocortisone and the risk of sepsis in neonates born extremely preterm.

Baud O, Lehert P; PREMILOC study group.Eur J Pediatr. 2025 Jun 14;184(7):419. doi: 10.1007/s00431-025-06248-9.PMID: 40515786 Clinical Trial.

From Warm to Cold: Feeding Cold Milk to Preterm Infants with Uncoordinated Oral Feeding Patterns.

Ferrara-Gonzalez L, Kamity R, Htun Z, Dumpa V, Islam S, Hanna N.Nutrients. 2025 Apr 26;17(9):1457. doi: 10.3390/nu17091457.PMID: 40362766 Free PMC article. Clinical Trial.

Impact of teleneonatology on time to goal temperature in outborn neonates with hypoxic-ischemic encephalopathy requiring therapeutic hypothermia.

Kaczor M, Hentz R, Youssef PE, Fine A, Fang J.J Perinatol. 2025 May 29. doi: 10.1038/s41372-025-02324-y. Online ahead of print.PMID: 40442292

Norepinephrine versus Dopamine for Septic Shock in Neonates: A Randomized Controlled Trial.

Mazhari MYA, Priyadarshi M, Singh P, Chaurasia S, Basu S.J Pediatr. 2025 Jul;282:114599. doi: 10.1016/j.jpeds.2025.114599. Epub 2025 Apr 17.PMID: 40252959 Clinical Trial.

All-cause mortality and infection-related outcomes of hospital-initiated kangaroo care versus conventional neonatal care for low-birthweight infants: a systematic review and meta-analysis.

Minotti C, Jost K, Aghlmandi S, Schlaeppi C, Sieswerda E, van Werkhoven CH, Schulzke SM, Bielicki JA.Lancet Child Adolesc Health. 2025 Jul;9(7):470-483. doi: 10.1016/S2352-4642(25)00130-0. Epub 2025 May 26.PMID: 40441171 Free article.

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Watch this week's Journal Club on YouTube 👇

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The transcript of today's episode can be found below 👇

Ben Courchia MD (00:01.218)

Hello everybody, welcome back to the Incubator Podcast. We're back today for an episode of Journal Club. Daphna, how are you?

The Incubator (00:07.72)

I'm doing well. have some articles that were left over from last time because you had such big hitters last time discussing the PDA and whatnot.

Ben Courchia MD (00:13.378)

Yeah, it's been,

Yeah, that article definitely made the rounds. There's been a lot of discussion about it. But like we said last time, it's nice to have these sort of goalposts of saying like, this is where we're going to plant the flag for now. And then let's see if we can move it. So yeah, and it's been a busy, it's been a busy, I think for us, especially from the editorial standpoint, it's busy, it's busy on the article front when there are such major reports coming out, because we also like, as you've seen on the podcast to review

The Incubator (00:19.615)

Mm-hmm.

The Incubator (00:29.789)

Yeah, for sure.

Ben Courchia MD (00:46.016)

some just smaller studies sometimes, but have very interesting questions or some very interesting findings. And unfortunately, obviously these have to take a little bit of a backseat when the AP comes out with a report on the PDA that sort of has to take a backseat. so our list has been piling up. So there's definitely a lot of articles to review and very excited about today. There's a lot of very interesting topics that we're going to touch on. without much further ado, we're going to get started.

The Incubator (00:50.119)

Yeah. For sure.

Ben Courchia MD (01:15.894)

I just wanted to give two quick updates to the audience. Obviously, we are processing the submissions for the annual giveaway. if you haven't heard anything from us, it's not like we will respond to everybody, but we're actually just tallying all the entries and so on and so forth. We are a notoriously inefficient group. So.

The Incubator (01:39.559)

Well, I think we prioritize Journal Club and board review and interviews, but we'll get there. We'll get there. Yeah, that's right.

Ben Courchia MD (01:44.876)

Yeah. I'm not. We'll get there. But I'm saying it's our fault. It's not nobody's else's fault. And then obviously the Delphi conference is open for registration and we're going to have more content coming your way about the speakers and the lineup. It's going to be very exciting. You're not going to want to miss this. Again, we're keeping this a very intimate type of conference. We are not going to have unlimited amount of spots. It's a limited seating.

plan on attending January 26 to 28, 2026. You're coming to sunny Florida in the middle of winter. It's always going to be pleasant. And we have never invested as much time and effort in the lineup and in the curation of the content. So it will be quite exceptional. That being said,

The Incubator (02:30.505)

People are already registering, so that's exciting.

Ben Courchia MD (02:33.102)

Oh yeah, no, and that's why I wanted to remind people. I don't want people to get into a position of like, I wanted to register and was too late. But there's really nothing we can do. We pick venues that have a certain number of seats. It's not like we're being, we're not being assholes and saying, oh, you can come in. It's like, there's a number of seats. After that, we can't because no, it's not, All right.

The Incubator (02:41.831)

Yeah. Right.

The Incubator (02:51.869)

Yeah, and I think it's good for people to know also as they are making their planning. We have a hotel selected, the Flow Hotel, which is very South Florida, but very comfortable. Even options for like people who want to like share rooms and stuff, want to travel together. So yeah, for sure. So we want to make sure that everybody's really comfortable, that there's a lot of flexibility. If you want to come with a group or you want to bring your family, that we can accommodate that.

Ben Courchia MD (03:03.713)

yeah.

Ben Courchia MD (03:08.558)

These are like mini apartments. Very nice.

Ben Courchia MD (03:19.69)

Yeah, so just so people know, when we say that, these rooms are very sort of a lot of wood, very relaxing, very nice views. And they're kind of little apartments, so you actually have some independence. There is a very nice gym. There's a very nice pool. There's some outdoors yoga area. When we say that it's going to be a relaxing conference where people will leave with more energy than they left with,

The Incubator (03:26.76)

Yes.

Ben Courchia MD (03:46.862)

that they came in with, then we truly mean that. And we pay a lot of attention to make that happen. All right, let's get going with the journal club. The first paper I wanted to review that is a very interesting one that I saw in JAMA PEDES. It's called Severe Neonatal Morbidity and All Cause and Cause Specific Mortality Through Infancy and Late Adolescence. First author is Hillary Graham. It's a study that is coming to us out of Sweden.

that examines the long-term mortality implications of severe neonatal morbidity. I think this is particularly relevant as we see more infants surviving the neonatal period, but potentially with significant health challenges. Now, while neonatal survival rates have dramatically improved, we're seeing more infants surviving the neonatal period, but experiencing morbidities that we know may have lasting consequences.

And what the authors point out is that identifying key morbidities during the perinatal and the neonatal period could help us target those at greatest risk for early life mortality. I think it's something that we cannot shy away from, but it's terrifying to talk about early life mortality for children. So in the paper, they talk about this concept of SNM, severe neonatal morbidity, that they say during the first 27 postnatal days has been identified

as an important health indicator, though it encompasses a variety of diagnoses and is often defined inconsistently across studies. Now, common severe neonatal morbidity diagnoses include IVH, they include extremely and very preterm birth, they include sepsis, all associated with an increased risk of morbidity and mortality. Now, previous research on this topic has shown striking findings that

I think we're all kind of aware of, when we actually look at the data, it's definitely not something that we talk a lot about. One study actually had demonstrated that infants with certain neonatal morbidities have a 10-fold higher risk of death in their first year. Another one found that...

Ben Courchia MD (05:54.494)

S severe neonatal morbidities, and I'm going to start using that interchangeably, is a strong risk factor for infant and child mortality up to five years of age and is significantly associated with higher mortality from conditions affecting the endocrine, the nervous, the respiratory, and the circulatory system. Now, what their authors are mentioning is that longer term follow up for specific S &Ms

subtypes and overall SNM beyond five years of age has been lacking with little known about cause specific mortality in that population. There's also no studies that has looked at sibling control analyses. So this group out of Sweden basically decided to examine the association between SNM during the neonatal period and all cause and cause specific mortality from infancy to adolescence using both population based and sibling controlled analysis. So the Swedish

group here in this paper basically did a population based study from 2002 to 2021. This is taking place in Sweden and it's leveraging a lot of the database that they have over there using the Sweden's comprehensive registry system cross linking the medical birth register with the Swedish neonatal quality register, the national patient register and the cause of death register via unique sort of this national identification number. Now,

Basically, the National Patient Register contains information on all inpatient diagnostic codes and procedures since 1987, which is kind incredible, and outpatient care from 2001. And the Cause of Register captures about 99 % of all death in Sweden since 1952. So quite incredible. So this basically allowed them to look at a final study population of about 2 million singleton neonates.

Now the main exposure that they are looking at was the occurrence of severe neonatal morbidity among all life-borne neonates identified from birth through 27 days. SNM was defined as a composite event, consisting of five distinct categories with 19 specific subtypes. So they had respiratory morbidity, which included RDS, congenital pneumonia, BPD, other respiratory disorders, pneumothorax requiring drainage.

Ben Courchia MD (08:09.784)

They had a second category for S infections encompassing sepsis and bacterial meningitis. Then they had neurological morbidities included IVH, grade three to four, hypoxic ischemic encephalopathy, seizures, cerebral infarction, PVL, and neonatal hydrocephalus. They had specific respiratory procedures, including resuscitation requiring intubation and mechanical ventilation. And then they had a sort of catch-all category called other, including neck,

intestinal perforation, ROP, and birth trauma. So the researchers extracted all-cause mortality, primary primary underlying cause of death from the registry, and they categorized them based on different timelines. So you had death between 28 days and 11 months. That was called infancy. Then they had childhood deaths, one to four years of age, later childhood, five to nine years old, adolescence, 10 years and beyond. They looked at covariate

that in covariates that included neonatal characteristics such as the gestational age, birth weight, sex, being small for gestational age, five-minute apgar score, birth year, and any major malformation. Now what was very interesting was that in order to investigate potential confounding from shared family-related factors, they wanted to find out like, well, could these potential outcomes, mortality, terrible as it may be, could it be related to some familial component? Like maybe they have something genetic. And so they conducted a sibling-controlled analysis.

sibling pairs discordant on their prevalence of SNM. Again, SNM standing for I always have severe neonatal morbidity exposure were included with the model adjusted for infant factors and maternal factors, including maternal age, parity, smoking status, cohabitation status, educational level, pre-gestational diabetes, BMI, pre-gestational hypertension, and smoking status. So was very interested in that particular aspect also of that secondary analysis.

So let's dive into the results because I think they are very interesting as we mentioned of the 2 million live born Singleton infants included in the study, 49,225, that is 2.4 % had a diagnosis related to severe neonatal morbidity within the first 27 postnatal days. Infants with S were more likely to be preterm, they were more likely to be male, they were more likely to be small for gestational age, they were more likely to have a lower five minute ABGAR scores.

Ben Courchia MD (10:32.878)

and they were more likely to have major malformations compared to those without severe neonatal morbidity. Severe neonatal morbidity prevalence was also higher in infants of mothers who were young, 19 years or younger, nolly, Paris, less educated, living alone, smoking, or who had an elevated BMI or who had pregestational diabetes or hypertension. Now, during a follow-up period ranging from 28 days to up to 21.2 years,

3,618 children died with an overall mortality rate of 0.16 per 1,000 person years. Now here's the critical finding. Children with severe neonatal morbidity had a dramatically higher mortality rate of 1.81 per 1,000 person years compared to 0.13 for those without any morbidity.

Now in adjusted models over the entire follow-up duration, children with severe neonatal morbidity had a 5.92 fold, I'm sorry, I'm butchering this, almost a six fold higher adjusted hazard ratio of mortality compared to children without severe neonatal morbidity. Mortality rates were elevated for all types of morbidities, but some were particularly severe.

So compared with children who didn't have any severe neonatal morbidity, the adjusted hazard ratio for mortality were over 10 fold higher among infants with other respiratory disorders, meningitis, severe IVH, HIE, seizures, cerebral infarction, PVL, hydrocephalus, neck, SIP, and mechanical ventilation. Neonatal neurological conditions were the leading morbidity associated with a almost 18 fold increase.

in all-cause mortality after 28 days of life. I mean, these are staggering numbers. The study revealed significant sex differences as well in cumulative hazard estimates for all-cause mortality. And what was very interesting was that we tend to think that, rightfully so, that survival rates for female infants in the NICU is usually higher than male. But total mortality in that cohort was higher in female children compared with male children.

Ben Courchia MD (12:50.508)

the adjusted hazard ratio for all-cause mortality were 7.28 in female children compared to about five in male children. In particular, the association between severe neonatal morbidity and neurological morbidity was stronger in female children compared to male children. So stratified analysis by gestational age indicated that among those who had a severe neonatal morbidity, the mortality rate was higher in children that were born preterm compared to those born term.

And that is probably expected. However, compared to those without severe neonatal morbidity, the association between morbidity and mortality was stronger in term infants with an adjusted hazard ratio of 7.16 compared to preterm infants with an adjusted hazard ratio of 3.51, highlighting the fact that when term infants run into problems,

it can have even more dramatic consequences than sometimes in other term infants, in preterm infants. The study demonstrated that severe neonatal morbidity was associated with a higher mortality after 28 days of birth with associations persisting for several years, but weakening over time. So compared to a cohort that had no morbidity, babies who had some severe neonatal morbidity was associated with adjusted

hazard ratio of 7.66 at 28 days to 11 months, 5.2 from one to four years, 4.98 five to nine years, and 2.28 at 10 years or beyond, as you can see, sort of tapering over time. Importantly, infants with neurological or respiratory procedures had elevated mortality risks even after 10 years compared to those without severe neonatal morbidity. So I'm gonna wrap up by talking about the sibling analysis that we alluded to earlier on.

They included 32,000 children with morbidities versus their full siblings without any morbidity and revealed similar association as in the population analysis. The sibling analysis showed an adjusted hazard ratio of 4.33 compared to the overall population result of 5.92. And so among the SNM subtypes in the sibling analysis, all associations except respiratory distress syndrome and BPD were similar.

Ben Courchia MD (15:09.346)

to those in the primary analysis, though with some attenuation of estimated hazard ratio and lower precision, which is so interesting because it looks like there might be some genetic component to the respiratory pathology and maybe the extent, right? mean, if a family has, I'm giving an example that they didn't speak about that. This is me going on a limb here, but like a family of severe asthmatics that may put a baby that then has some type of morbidity in the NICU at an even higher risk of mortality down the road compared to someone who's born in a family of

quote unquote, perfectly healthy lungs kind of situation. So I thought that was kind of interesting, even though the data is kind of limited. So in conclusion, the author is saying that the cohort demonstrates that infants with severe neonatal morbidities who survived the neonatal period experienced increased risk of mortality into childhood, but also in adolescence. Neurological morbidities and respiratory procedures are the major contributors to both short-term and long-term mortality.

and efforts to further prevent severe and neural morbidity, ensure early identification, provide long-term follow-up, I think that's the key, may help reduce mortality and inform discussions with families regarding prognosis and follow-up needs. Daphna, what are your thoughts? It's the kind of data I would be terrified to present to families in the NICU.

The Incubator (16:21.031)

Yeah. Well, I mean, I think it's not unexpected information, but I think it's really important when we talk about long-term outcomes. It's kind of this like cumulative effect, you know? It's not just gestational age. It's not just birth weight. And I sometimes feel like we have this sense, especially for people who aren't doing follow-up, wow, like we got this very sick baby to the end post. They're going home.

And that's great. That's wonderful. I mean, we are making extraordinary strides on getting babies to discharge. But that cumulative effect of these morbidities and the impact on long-term mortality is impressive. And I think we need to keep that in mind and we have to keep working on how do we safely transition these babies home and what types of resources do they have? I mean, you and I both know in our area, for example, these medically complex kids, mean, home nursing is...

Ben Courchia MD (17:01.741)

Mm-hmm.

The Incubator (17:18.577)

a disaster, you know, so we really have to figure out how to optimize those things. And I was especially like you interested in the sibling data. You know, we've got a special event for Delphi specifically for multiples. And so it was interesting to see that as well.

Ben Courchia MD (17:38.414)

Mm hmm. Yeah. Yeah, I think that I think that, like you said, when you compound everything, Sweden has a very robust sort of social health care system. So when you compound the fact that how difficult it is, at least I'm talking for ourselves, for parents to actually go to these multiple appointments to get access to the different sub specialist with insurance issues, lapsing and so on and so forth, it definitely probably means that odds are probably higher in a setting like ours. Again, this is a very

Again, this is Sweden, which is one of the leading countries when it comes to neonatal care. So we're not talking about really a underserved sort of really emerging field of neonatology. These are the guys who actually know what they're doing. These are the Scandinavian teams that we inspire ourselves to strive for. so it's a...

The Incubator (18:16.415)

Yeah.

The Incubator (18:32.479)

Yeah, and the social networks there are quite robust, You know, parental leave and universal health care and...

Ben Courchia MD (18:35.638)

Yeah, yeah, no for sure.

I mean, wouldn't even know the state of our situation here in the US would be like, how would we even capture the data? I mean, just like, would we able to capture the data? How many times you hear of a baby who has somehow appeared at an outlying ER that may not be affiliated with your healthcare system? And it's like, oh my God. So anyway, very interesting data. Yeah, very interesting data. All where are you taking us next?

The Incubator (18:44.861)

Yeah. Yeah.

The Incubator (18:57.726)

Neat.

The Incubator (19:01.375)

All right, well, I had this paper that we can, hopefully we can reduce some of the morbidities. It's an active pediatrica. It's entitled, prone positioning was associated with less hypoxemic events and improved feeding tolerance in preterm infants. Lead author Bettina Bonhorst, senior author Carolyn Bone. This is coming out of Germany. And so basically what they wanted to look at was how did positioning

affect cardiorespiratory events. So apnea, bradycardia, and hypoxemia, that's the right word, which we know are very common in preterm infants. And we are learning that the frequency and especially the severity of hypoxemic events are impacting neurodevelopmental outcomes.

It's a small study, I will start by saying that, but between May 2016 and July 2018, they did a single center prospective randomized two arm crossover study at Hanover Medical School, their tertiary NICU. And they enrolled preterm infants with gestational age of less than 32 weeks at birth and less than 34 weeks at post menstrual age at the time of the study.

And the babies had to be having some of these clinical events. So more than six episodes of hypoxemia, less than 80 % and bradycardia less than 80 beats per minute in six hours. That's not a small amount of events. It's quite a large number of events. They excluded babies with congenital malformations, intestinal pathology or babies. They write here need for noninvasive positive pressure ventilation. So these are babies on

like NIMV or babies on mechanical ventilation. So all of these babies were extubated. And in terms of breathing support, then they were on room air, they were receiving supplemental oxygen, or they were getting high flow nasal cannula or CPAP. And importantly, the ventilatory support did not change for any particular baby over their study period.

The Incubator (21:19.643)

though some babies may have needed intermittent adjustment if they had a prolonged event. So basically the patients were then randomly assigned using random number generator to either group A, which was prone, or group B, which was supine as their starting position. Then each patient spent 12 hours documenting events in their starting position.

They had a 12 hour washout period and then they switched positions between the two recordings. So then they looked at all of the events for these babies. So for baseline data, again, I told you they had 48 patients, the median gestational age was 26.9 weeks with a range of 24.4 to 30.3.

weeks gestational age and a mean birth weight of 884 grams plus or minus standard deviation of 250 grams. And at the study patients had a mean post menstrual age of 31.7 weeks and a current weight of 1,273 grams. So each group had 24 patients. The demographics were pretty well matched in particular for gestational age.

But I will highlight that the median weight at study entry was significantly lower in group B, which was the prone group. A median weight at enrollment of 1,163 grams compared to group A, 1,378 grams. And I think that's important because remember we're comparing. So group A is

prone, group B supine, but the group A babies, the prone group, had a higher median birth weight. Okay. The total number of hypoxemia and bradycardia events did not appear affected by the starting position, and there were no carryover effects in any of the secondary outcomes.

The Incubator (23:35.709)

So the primary outcome they were looking for was a cumulative frequency of hypoxemia and bradycardias per hour. And they found that this was significantly decreased and almost halved in the prone position compared to the supine position. So the median frequency supine was about 17.6 compared to prone 8.3. And this decrease was primarily a result of an almost halving total number of all hypoxemias in the

prone position. So the prone position impacted both moderate, sats of kind of 85 to 80 % and severe, so sats less than 80%. So they showed an improvement in both types of hypoxemia. The occurrence of bradycardias did not differ between the two positions. So that was not statistically significant when they looked

at those findings individually. They also had a number of secondary endpoints. So they looked at the total time spent in hypoxemia. This was significantly decreased and more than halved in the prone position. So the cumulative duration supine was about 37 and a half minutes compared to prone, which was 16.3 minutes. And this was particularly relevant for those, again, severe hypoxemia is less than 80%.

The supine group spent about 22.9 minutes compared to the prone group 9.1 minutes. They showed a trend toward a worsening of severity of hypoxemia in the supine position by about 6%, but this was not statistically significant. They also wanted to look at the median duration per event. This did not appear to be statistically significant either.

basal parameters for all the patients. So they wanted to look in particularly at that quiet sleep. So median heart rate, respiratory rate, occurrence of periodic breathing or the need for supplemental oxygen delivery did not differ significantly between prone and supine positions, but they looked at the median and the minimal baseline SPO2. These were significantly increased in the prone positioning.

The Incubator (25:57.663)

So whereas the median saturation for supine was about 96.3%, in the prone position it was about 97.9%. And then the minimum saturation, the average minimum saturation in the supine position was 92.9 % and the prone position 95.1%.

I told you early on they were also looking at how this might impact feeding. So they looked at gastric residuals from the previous meal. And we're moving away from checking gastric residuals, but this was interesting. The gastric residuals from the previous meal was significantly lower in the prone than in the supine position, though they were hoping to reach a 20 % threshold. But the median remaining gastric residuals in the supine was about 3.75 % of the previous meal.

compared to the prone where some babies had nothing left. So that was the median gastric residual. And then they looked at the maximum gastric residuals. And this was also statistically significant in the supine. It was about 12 % of the previous meal. In the prone, it was about half of that, 6 % of the previous meal.

So I told you a lot of good things about the prone positioning, but interestingly, the frequency of apneas was increased in the prone position compared to the supine position. So median number per hours in the prone was 1.2, and the supine was about 0.4. And this was statistically significant, though the median duration per event did not differ between both positions.

So again, I want to highlight that it looked like the prone positioning did offer quite a number of benefits, but this was in a group of babies that were slightly bigger. And we know that's an important factor for outcomes in the NICU, especially in this early population. But I think it's interesting.

The Incubator (28:05.151)

I think there are still units that aren't using prone positioning like at all. I was kind of surprised to know that. And so I thought this was a useful, useful paper.

Ben Courchia MD (28:16.078)

Yeah, I mean, it's always interesting when you have a small study like this that is able to reach a statistical significant result. It means that the difference that they were able to achieve is staggering. And I think that this is something that should be looked at. Again, as you mentioned, they have a small number of patients, and that's OK. But they're able to decrease the number of events by 50%. That is not benign. Now granted,

The Incubator (28:18.943)

Yeah.

The Incubator (28:34.388)

Mm-hmm.

Yeah, by 50%.

Ben Courchia MD (28:43.19)

I think that this is data that continues to corroborate what we know about prone positioning. And it doesn't obfuscate the issue of prone positioning, which is we can't leave these babies prone 24 hours a day. But it is an intervention that is at your disposal. Use it judiciously.

The Incubator (28:47.913)

Mm-hmm.

The Incubator (28:53.599)

all the time. That's right.

The Incubator (29:00.199)

Yeah. I know it's interesting too about this gastric residuals. mean, well, could that help with some of our reflux type problems? I don't know. I mean, they didn't prove that, but it's interesting. We don't, we don't take residuals, but I thought that was interesting.

Ben Courchia MD (29:11.864)

Do you even check residual,

Ben Courchia MD (29:19.564)

Yeah, very interesting indeed. Okay. All right. The next paper I have for you, The Risk of Sepsis in Neonates, Born Extremely Preterm. First author is Olivier Beaux, who is on behalf of the Premiloc study group. I had the pleasure of interviewing Olivier with Gabriel Altet on the French edition of the podcast. If you are French speaking, go listen to it. He is a brilliant mind and who has done a lot of work with Christy Waterberg.

on the use of hydrocortisone. Christy mentioned him repeatedly during our interview with her on the English edition of the podcast. So what the team at the Premiloc study group wants to look at is examining basically a critical safety concern surrounding the use of prophylactic hydrocortisone in extremely preterm infants. Now, this is basically a post hoc analysis of the Premiloc trial.

that addresses one of the main barriers of implementing prophylactic hydrocortisone as standard of care. Because despite the evidence that has been published on hydrocortisone, and because of the long-term outcomes associated with the use of hydrocortisone, it's not really been sort of favored as the standard of care. So now the group mentions obviously that the increased susceptibility to infection in preterm infants is primarily due to a deficient immune system, an immature epithelial barrier, increased need for invasive devices.

And that extremely low gestational age neonate population or LGAN as they are known is at a particularly high risk for late onset sepsis with approximately 20 % of neonates experiencing at least one culture proven episode prior to discharge according to certain data. Now prophylactic administration of low dose hydrocortisone in that population has been shown to improve survival without BPD and to reduce the need for treatment of PDA and reduce pre-discharge mortality.

As a result, it's increasingly being introduced as a standard treatment in certain NICUs. know that Olivier and some of his colleagues adamantly believe in the use of prophylactic hydrocortisone for this very vulnerable population. But they are being honest in the background section, mentioning that some systematic reviews support the benefit from early hydrocortisone treatment, particularly in infants with a gestational age at birth above 25 weeks. There's concerns regarding safety.

Ben Courchia MD (31:47.63)

And although some neonatal centers have incorporated the Premiloc regimen into local practice, prophylactic hydrocortisone is not currently recommended as standard of care. Now, the major safety concern that is being brought about is from an individual patient data mid analysis of the main trials using prophylactic hydrocortisone to prevent BPD or neonatal death, which showed an increase in risk of late onset sepsis with an odds ratio of about 1.34, particularly in a subgroup of infants born between 24 and 25 weeks of gestation.

where the odds ratio is 1.87. Now the adverse event is undoubtedly a barrier to further implementation of this prophylactic strategy. Surprisingly, they say this potential adverse event did not result in additional risk for neonatal mortality, mortality at discharge, or neurodevelopmental disorder at two or five years of age. Real world data have come from single center retrospective cohorts in the UK, in Canada, in the US.

and more recently Sweden. So the purpose of this study is to reanalyze the Premiloc dataset to predict late onset sepsis incidence from baseline conditions and examine perinatal factors influencing the incidence of late onset sepsis and assess the potential interaction arising from prophylactic hydrocortisone exposure. So like we said, post-doc analysis of the Premiloc trials, was

double masked placebo controlled multi-center randomized trial that basically enrolled extremely preterm infants delivered before 28 weeks of gestation from 21 perinatal centers in France. Eligible infants were randomly assigned to receive either prophylactic, low dose hydrocortisone or placebo starting within 24 hours after birth and for a total duration of 10 days. The primary endpoint.

of the original Premiloc trial was a composite endpoint defined as survival without BPD at 36 weeks of post-menstrual age. Now, the primary outcome of our paper today of this post-doc study is the risk of late onset sepsis defined by a positive blood culture or a diagnosis of pneumonia with significant clinical deterioration detected after day three, according to the international definition of late onset sepsis.

Ben Courchia MD (34:03.872)

Pneumonia specifically was defined as a chest X-ray showing pulmonary opacities associated with the presence of positive culture in the airway and clinical deterioration after day of life three. Late onset sepsis occurring after day seven or day 10, that is at the end of the hydrocortisone exposure, was considered as an endpoint for the sensitivity analysis only. Now, the researchers categorized respiratory support at baseline into three categories. You had...

Respiratory support at baseline RSB that was considered mild if you were on non-invasive ventilation with less than 30 % FiO2. You were moderate if you were on mechanical ventilation with an FiO2 less than 30 % or severe if you were on mechanical ventilation with a need of 30 % or greater. Secondary neonatal outcomes specifically included the total number of days the infant was mechanically ventilated, age at weaning from respiratory support, PDA, and treatment for PDA medical or surgical. So in terms of the data,

They were able to basically get most of the babies from the Premiloc cohort. So out of the 523, they were able to do that analysis on 519 of them based on like some consent that were pulled, but nothing really crazy from that standpoint. A relative difference of more than 15 % between the compared group was found for general anesthesia and gestational hypertension only. And there were no other significant differences.

between other variables in the baseline characteristics between the babies who did receive hydrocorizone versus the ones who did not. So let's get into some of the outcomes. Overall, the proportion of late onset sepsis reported in the population was 27.2 % after day three, 23 % after day seven, 17 % after day 10, with a significantly higher proportion in the hydrocorizone treatment group. The case fatality rate likely attributable to late onset sepsis

was 23 % in the placebo group and 26 % in the hydrocorizone group. Now using a step-wise strategy to study the occurrence of late onset sepsis occurring after day three, the main analysis provided basically three main predictors at baseline for an increased incidence of late onset sepsis. A decreased risk of late onset sepsis was observed with increased gestational age with a relative risk of 0.772 per week, vaginal delivery,

Ben Courchia MD (36:26.306)

was also associated with a decreased risk, with a relative risk of 0.611, and perinatal asphyxia, which showed a trend toward increased risk with a relative risk of 1.66. Among covariates occurring during the first postnatal week, supplemental steroids given after 10 days of treatment with prophylactic hydrocortisone, but before any form of sepsis occurred, were found to be associated with a decreased

risk of LOS. So the supplemental use of hydrocortisone somehow lowered the kids who did get supplemental hydrocortisone had lower risk of developing sepsis. For the effect of hydrocortisone treatment on the risk of late onset sepsis, the model predicting the occurrence of sepsis found in the previous section, these three variables, that when it was used, the hydrocortisone effect in adjusting the risk of sepsis for gestational age, vaginal delivery, perineal asphyxia, and even supplementary corticosteroids

The proportion of late onset sepsis was 24.5 % with a standard deviation of 9.8 % across the centers, giving a variation coefficient of 0.33. The effect of the three main adjustment variable did not change and adjusted for these covariates. The researchers found a non-significant hydrocortisone effect with a relative risk of 1.04. When they investigated late onset sepsis occurring between day three and the end of the course, day 10,

and adjusted the same model, they find that treatment effect with a relative risk of 0.96. So almost no difference. The researchers also performed the competing survival analysis, which was very interesting using the fine and gray model considering death and late onset sepsis as competing endpoints. And after adjustment for the baseline variables associated with the risk of late onset sepsis, again, gestational age, delivery mode, perineal asphyxia, the effect of prophylactic hydrocorizone.

on late onset sepsis was found not to be statistically significant while competing death was reduced by the treatment with a hazard ratio of 0.427. And so the conclusion of this tedious data analysis is that considering basically baseline risk factors, the risk of LOS of late onset sepsis is not significantly different between the group that receives prophylactic hydrocorizone and placebo. And this competing survival

The Incubator (38:29.448)

Just now.

Ben Courchia MD (38:43.98)

by fine and gray analysis suggest that death was reduced by the prophylactic use of hydrocortisone without a significant effect of the treatment on the risk of late onset sepsis. These results obviously should be confirmed, they say, in larger real-world population-based cohort studies. And I think that, to me, it's very interesting because, again, it's Olivier just really standing behind the data and standing behind the Premiloc trial.

To me, I don't know how I take this data at face value, but I think the underlying message is the right one, in my opinion. Every baby is not the same. There are baseline risk factors that will make a baby more likely to benefit from this treatment versus others, whether it is exactly the gestational age, which, again, we kind of know. But vaginal delivery, whether it is perinatal asphyxia, and so on and so forth.

The Incubator (39:23.903)

you

Ben Courchia MD (39:40.632)

Those are very interesting to investigate. I think that maybe it is a way of the Premiloc team to sort of move away maybe from a more wholesale prophylactic use of hydrocortisone and they'd be saying, maybe there is a subpopulation that would truly benefit the most and benefit the most from the benefits of hydrocortisone, all the while not being exposed to potentially some of the adverse effects that we have been concerned about. So I think this is very interesting.

The Incubator (39:54.931)

Mm-hmm.

Ben Courchia MD (40:08.718)

And that's why I wanted to review it.

The Incubator (40:12.223)

Well, and I think, I mean, it's always complicated when you are like interrogating data, right? That wasn't intended for that purpose. But I mean, when you have studies with such large data sets, I almost feel like you're obligated to do some of this additional work because, know, everybody's done the work, the patients have been enrolled, the information is there. And so we should be looking at those.

Ben Courchia MD (40:17.291)

yeah.

The Incubator (40:37.393)

if nothing to just generate new, you know, hypotheses and go from there. But I do think this is relevant, right? People are worried that if we give steroids very early at a baby who may be at risk for infection, will, you know, will we compromise the immune system and they'll be more likely to be infected. So, I mean, I do think this targets some concern people have about early hydrocortisone.

And I think one of the groups that we think are most likely to benefit are those babies with the history of coriamnionitis. So I think this is especially interesting as well.

Ben Courchia MD (41:17.868)

Yeah. And I just want to mention basically, I mean, obviously I invite everybody who hasn't read the Premiloc trial that was, what was it? It was published in the Lancet, I believe. 16. Yeah. I think that in the Premiloc study, what was interesting obviously is the fact that in that particular population, when they reported the severe adverse events, they didn't see any difference in, in, in the, in the change in the adverse event, except for the fact that babies who received

The Incubator (41:23.059)

Yes, ma'am.

Yeah,

Ben Courchia MD (41:46.638)

hydrocortisone had a lower mortality rate prior to discharge. And when it comes to sepsis, the numbers were fairly the same. They had about a 31 % rate of late onset sepsis in the hydrocortisone group and 25 % in the placebo group. And it's, I think you were saying they're interrogating their data, but I feel like also there's that sense of, well, these other mid-analyses are doing that, right? And these individual patient mid-analyses, so I think...

The Incubator (42:10.558)

Uh-huh.

Ben Courchia MD (42:13.644)

This comes as a response potentially to that. But it is tedious work for sure. And what you do with that information, I don't know. I'm curious to see what the response on Twitter is going to be to this because hydrocortisone divides more than anything in our field.

The Incubator (42:26.419)

That's right.

For people who want to listen to our interview with Dr. Waterberg, was episode 53. She took a chance on us when we were still pretty early coming to chat with us on the podcast in that first year. So people can take a look at that. Yes, we were starstruck as it were. I had another interesting paper. actually in the journal Nutrients.

Ben Courchia MD (42:45.346)

That was a big get.

Ben Courchia MD (42:51.566)

Well, yeah.

The Incubator (42:58.559)

And it's entitled, From Warm to Cold, Feeding Cold Milk to Preterm Infants with Uncoordinated Oral Feeding Patterns. Senior author, Nazee Hanna. And this was done in New York, a collaboration between NEOs at NYU and the University of Arkansas. So basically what they were...

The background is kind of interesting. So they recognize that in adults with dysphagia, cold liquids enhance swallowing by stimulating these sensory receptors in the pharyngeal mucosa. So they had previously shown that feeding infants with cold liquid had reduced dysphagia in preterm infants. But I think a lot of units are still not using cold.

feeding. So that's something that they wanted to look at. So basically they selected these infants that had kind of this concern for disorganized feeding and then wanted to compare cold milk or room, not even warm milk, room temperature milk. So I thought that was really interesting. I will go ahead and give you the, the

punchline early that the predominant results of the study are negative. But I think that's interesting in and of itself because, you know, we spend a lot of time warming milk. So I thought that was interesting, but I'll give you some of the details. So they enrolled preterm infants less than 37 weeks gestational age at birth.

with a post-monstral age of 34 to 42 weeks. So they were targeting these babies who were working on PO feeding at the time of enrollment. And they had to have a documented uncoordinated feeding pattern using the infant-driven feeding scales or the IDFS, which they were routinely using in their unit. Infants were excluded if they had a growth restriction, history of GI pathology like neck, gastroschisis, malabsorption, diarrhea, or emphyseal.

The Incubator (45:17.151)

They also excluded babies with NAS because of its potential effect on feeding behavior. So each participant then was exposed to two oral feeding conditions. So either room temperature, which was 68 to 77 degrees Fahrenheit, or cold temperature, 39 to 48 degrees Fahrenheit in a randomized crossover design. So babies...

were started with one, they had this washout with a number of feeds, within another 12, within a 12 hour period, they were given the other feeding regimen, the other temperature. So that way they had enough time to warm back up if it was cold, but to reduce, you know, much change in clinical status.

So in the room temperature, the control condition, infants got their kind of usual milk, either formula or breast milk at room temperature. And then again, the cold condition, it was never brought to room temperature. Feeding was performed by a trained research member with infants positioned in this side lying posture using a slow flow nipple.

They studied the babies. They wanted to look for other signs of cold stress. So they looked at auxiliary temperatures and any baby who already had an NG tube in, they measured the temperature of the gastric contents. They didn't put NG tubes in babies who didn't have them because they thought this was like an unnecessary kind of trauma. They measured the temperature of the gastroaspirate.

as the baseline and room temperature and then the cold temperature, they looked at it at 1, 10, and 30 minutes post-feeding to look at return to baseline. They looked at other clinical signs of cold stress, so tachypnea desaturation, apnea, bradycardia, increased gastric residuals, and MSS. They also used Doppler ultrasound, not in the whole cohort. This was a small study, but in even smaller subset of the patients.

The Incubator (47:32.659)

They looked at Doppler ultrasound to look at superior mesenteric artery blood flow as a marker of intestinal perfusion, especially given concerns about feeding cold milk potentially. And for the Doppler assessments, any baby who was studied by Doppler had kind of a one hour before feeding baseline and then 30 and 60 minutes after each

feeding. Okay. They, in terms of the feeding performance assessment, they used a number of parameters and they kind of evaluated them at five minute intervals. They used the oral feeding skills score and they used, like I told you, infant driven feeding scale.

They also use two additional subjective measures, so stress cues and the need for pacing, using the stress scale and the pacing scale. So they're subjective, but there are scales to evaluate that. And I told you they were looking for other cardio respiratory events. So a small study, 26 preterm infants, and they had five infants who underwent the Doppler assessments to evaluate mesenteric blood flow.

Median gestational age at birth was 31 weeks and six days. The median day of life at enrollment was 28 days with a median post menstrual age of 36 weeks and one days. All of the babies had previously done some oral feeding with a median of eight days of partial oral feeding before enrollment. So 14 infants started with room temperature, 12 infants started with the cold temperature, and again, it was a crossover design.

So there was no significant reduction in axillary body temperature. The gastric temperature measurements, again, were only performed in babies who already had an NG tubes. This only included seven babies. And by one minute after feeding the temperature, the cold milk had increased from what it was fed at 39 to 48 to an average of 83.3.

The Incubator (49:59.279)

basically upon reaching the stomach, so within one minute. The gastric content temperature following the cold feeding was only 3.6 degrees lower than that observed after room temperature feeding at the one minute time point, and this was statistically significant. In terms of all those other signs of cold stress, babies didn't have any difference between the two groups.

Again, in the small group of babies who had a superior mesenteric blood flow measurements, there were no significant differences between feeding types. And then feeding assessment. So there was no statistically significant difference in the OFS scale levels between the two feeding conditions and other objective measures. So proficiency, so looking at the percent of volume ordered,

the rate of transfer and the overall volume did not differ significantly. Subjective assessments of stress cues and the need for pacing showed no significant difference. However, they did find one difference. So coordination of sucking, swallowing and breathing is measured by the infant dysphagia feeding scale demonstrated a statistically significant improvement with the cold temperature as compared to the room temperature.

And the mean IDFS quality score was 3.2 with room temperature and 2.6 during the cold temperature condition. So basically better coordination during the cold temperature feeding. I had it pulled up here. Sorry, the infant dysphagia scale for people who are not familiar with it. Oh, let's see if I can find it for you.

Ben Courchia MD (51:52.61)

You can, you can...

The Incubator (51:53.107)

But I mean, basically.

Ben Courchia MD (51:56.962)

I'll find it.

The Incubator (51:57.949)

Yeah, you find it. I just wanted people to know like what the scale numerical values are. But this was a kind of a reasonable improvement. They wanted to look at like what is the clinical relevance. So they looked at the babies individually. So 10 out of the 21 infants showed between a one to a three point improvement. 10 showed no change and only one infant had a one point decline when being fed the cold milk.

compared to the room temperature milk. So some of the feeding parameters didn't change, but I think their hypothesis was that it would impact dysphagia and they did show a statistically significant improvement in that. So again, a small study, but I think they did a really good job at looking at some of those balancing measures that I think people are worried about. And so many of our babies are staying for a long time.

Ben Courchia MD (52:52.418)

Mm-hmm.

The Incubator (52:57.577)

just for feeding readiness. And so it's interesting to look at what other ways can we modify feeding to potentially improve feeding outcomes. yeah, sorry, I know.

Ben Courchia MD (53:09.472)

I couldn't find the, I'm afraid I'm going to pull up a table that is not the right one, but it's a very interesting. mean, I think you, you, you, shot our enthusiasm a little bit in the beginning by, giving the punchline. And I think that maybe a lot of nurses who are listening, who are looking like, my God, I'm not going to have to, to thaw the milk as much as the before save a lot of time, but it's an interesting, it's an interesting approach. And, and I think that, especially for the room temperature milk,

The Incubator (53:18.783)

Bye.

The Incubator (53:26.481)

If you

Ben Courchia MD (53:37.966)

What do you think, based on the data, obviously this is a relatively small study, but the question is, is this something you would try? Let's say a baby is stuck a little bit, is learning to like, would you say, try room temperature and see if that makes any difference?

The Incubator (53:56.671)

Well, you know, it's interesting because in our unit, we don't even use room temperature milk. I mean, it's slightly warmer than room temperature. But I think so, especially a baby who is at that point, we have babies that are full term that are still struggling to feed and plenty of babies who are full term at home are getting cold milk.

so yeah, I think in a baby where we're really stuck, maybe there are some babies that, that would, would benefit from this. So, yeah, I think, I think so. Yeah.

Ben Courchia MD (54:31.352)

Would you try code?

Yeah, because I think that's the other thing that I sort of didn't mention. yeah, I we all probably, I think we're all using similar machines and stuff. our milk is probably on the warmer side than on the colder side. And I feel like as a human, we may want to feed a warm bottle of milk to our big. It feels like we should, exactly. But I'm just curious if you might say, all right, let's try a cold bottle.

The Incubator (54:41.565)

Yeah.

The Incubator (54:51.335)

It feels like we should, right? Yeah.

The Incubator (55:02.035)

Yeah, I think if you're really stuck, especially in a baby, again, they were using these kind of late preterms, I mean, they were premature babies who are now at feeding age. I think people are still always concerned about this cold stress or mesenteric, you know, ischemia. I don't think they had enough numbers to really look at that, but...

Ben Courchia MD (55:24.088)

I mean, it's a chilled glass of milk. I mean, it's like five to 10 degrees centigrade.

The Incubator (55:29.151)

which as an adult is delightful. Okay. Nobody wants warm milk once you hit a certain age. So I think I would try it, especially I think in a baby who's stuck at term corrected, you know, and see.

Ben Courchia MD (55:31.437)

Hahaha

Ben Courchia MD (55:42.028)

Interesting.

Ben Courchia MD (55:48.642)

Yeah, especially when you have, mean, these are the interesting interventions where you don't really need a lot of data to safely just try like, just like when we talk about all these interventions regarding like music in the NICU, it's like, how much data do you need to put like a very, very soft lot of buy to the babies? think it's interesting. All right. I'll look out for the babies. You try this on and see if they're working.

The Incubator (56:11.185)

And, and, you know, we've all been there, right? Yeah. My own home at you as somebody had pumped milk and the baby's screaming and you're like, I guess I won't warm it. I'll just feed it and see how goes. You know, so babies are getting cold milk at home, right? So.

Ben Courchia MD (56:20.908)

Yeah, yeah, no, no, that's true.

They are getting cold milk. even, yeah, I agree. I agree. All right. All right. We have a few more articles to go through. I really wanted to talk a little bit about, I have two more articles. I'm going to give us a little bit of a break. I wanted to talk a little bit about something that is.

The Incubator (56:28.607)

You

The Incubator (56:33.279)

Mm-hmm.

Ben Courchia MD (56:46.318)

a subject we don't talk about often, which is it's a paper that I found in Journal of Perinatology. It's called Impact of Tilly Neonatology on Time to Goal Temperature in Outborn Neonates with Hypoxic Ischemic Encephalopathy Requiring Hypothermia. First author is Mark Caxor and last author Jennifer Fang, who is on our lineup for the Delphi Conference. But it is a topic that we're very interested in. And this group out of the Mayo Clinic

in Rochester, basically was examining how telemedicine technology can improve outcomes for basically one of the most time sensitive interventions in neonatology, therapeutic hypothermia for HIE. So HIE, the background is interesting. We know most of it. It remains a leading cause of neonatal morbidity and mortality worldwide. Therapeutic hypothermia is pretty much the only intervention that is available at this time, and it relies on prompt initiation to optimize neuroprotective effect.

And this can be logistically challenging for neonates that are born at non-tertiary centers and that require transport to regional centers. These are like what we would call the outborn population. Now, outborn neonates that require hypothermia for HIE, they've been reported to have higher rates of death, higher rates of seizure necessitate, necessitate, necessitating treatment. my God.

Gastrostomy to placement compared to neonates born at a hospital with a NICU and the ability to actually deliver therapeutic hypothermia. And so this highlights the critical importance of optimizing the care pathway for these vulnerable infants. Now, in terms of tele-neonatology, real-time audio-video telemedicine consultation with a neonatologist provided to surrounding community hospital is a potential means to accelerate this process by offering expert assessment and recommendations within minutes after birth.

Telly neonatology has been shown to increase the quality of high-risk newborn resuscitation. It's been shown in previous retrospective cohort study to demonstrating that perinatal asphyxia or encephalopathy was the admission diagnosis for 15 % of neonates who underwent consultation. And while utilizing Telly medicine to assess neonatal encephalopathy, it has been shown to be at the same time feasible.

Ben Courchia MD (58:57.89)

But it is unknown whether it could improve therapeutic hypothermia process in early and early health outcomes in these neonates. So the objective of the study was to assess whether teloneonatology can be associated with earlier achievement of gold temperature in outborn neonates with HIE that underwent cooling. And the secondary objective was to determine whether teloneonatology was associated with a reduced early neurologic morbidity or in-hospital mortality. This was a retrospective observational study of neonates who were born at community hospital.

and transfer to the Mayo Clinic for therapeutic hypothermia to treat HIE between 2013 and 2022. They have a bit of a description that the Mayo Clinic basically has a 24-bed level 3 NICU and a 34-bed level 4 NICU and basically approximately like 800 admissions a year. And all the neonates that we're going to talk about today are neonates that underwent cooling at the level 4. Now, the decisions regarding the initiation of therapeutic hypothermia for HIE were maced

were made based on the criteria from the NICHD and the Neonatal Research Network trial on cooling. The exposure of interest in the study was the consultation via tele-neonatology, which is a video telemedicine service that's available to outlying hospitals 24 hours a day, seven days a week, and that allows neonatologists to remotely assess and advise on the management of neonates at community hospitals. Now, during the study periods, subjects were admitted from 19 different community hospitals. 12 of the facilities

participated in Mayo Clinic's tele-neonatology program for at least some portion of the study period, while the remaining seven did not. In hospitals participating in the tele-neonatology program, the referring physician could choose between initiating a phone or a tele-neonatology consultation. Physicians at sites without tele-neonatology initiated a phone consultation with the neonatologist. Now, during the phone consultation, which served as the control group in that case,

the transport team could be dispatched by the neonatologist as soon as it was identified that the infant required a higher level of care. So you didn't have to hang up, call the transfer center, get the face sheet faxed over, and do a formal sign out. While you were on the phone, it's almost, I didn't say this, but it almost feels like they could press a button and activate transport. If they did not use the tele-neonatology consult, a separate phone call.

Ben Courchia MD (01:01:24.536)

by the referring physician was needed to activate the transport team. The primary outcome of the study was time from birth to the achievement of core temperature between 33 and 34 degrees Celsius, obviously being the goal for therapeutic hypothermia. Secondary composite outcome were early neonate, neurologic morbidity or mortality, including the presence of any of following electrographic seizures, evidence of significant brain injury on MRI and or death prior to an acute discharge or transfer.

Let's get into the results. So 77 neonates met eligibility criteria and were included in the study. these 42, 55 % of the cohort were in the tele-neonatology group. 35 others, 45 % of the cohort were in the control group. The baseline characteristics were generally comparable between the tele-neonatology and the control groups, with the exception of race, where there was a difference in distribution observed where there was 71 % of the patients who were white in the tele-neonatology group versus 83 % in the control group.

In terms of advanced airway placement in the delivery room, it occurred more often in the telionetology group at 31 % compared to only 20 % in the control. Whereas both groups had similar proportions that received the chest compression at 26 % in both groups and epinephrine was used in 7 % versus 6%. So I think that already is quite interesting, the ability to more readily rely on advanced airways.

The median time between the transport team being dispatched from the Mayo Clinic and arrival at the birth hospital was comparable between the group, surprisingly 50 minutes in the tele neonatology group versus 55 minutes in the control group. So I would have expected that to be a little bit more different in the tele neonatology group. The median time from birth to initiation of the telemedicine consult was 13 minutes and the mean consult duration was about 56 minutes.

Now for the primary outcomes, neonates in the tele-neonatology group achieved gold temperature in a median of 3.4 hours compared to 4.6 hours in the control group, representing a mean ratio of 0.75. This difference remains statistically significant when adjusting for patient acuity using blood gas pH with an adjusted mean ratio of 0.76. A few more results. The study also conducted a sophisticated causal inference analysis using directed

Ben Courchia MD (01:03:42.43)

a a select graph to understand the mechanism behind this improvement. And they identified the two key mediating factors. The time from birth to activation of the transport team was reduced in the teloneonetology group, occurring at a median of 23 minutes compared to 61 minutes in the control group. you see, we're all struggling with the same thing. We activate it, but it takes some time to get there. Additionally, infants in the teloneonetology group had significantly

greater odds of having passive cooling initiated prior to arrival of the transport team, 57 % versus 14 % in the control group. Now, in terms of safety concerns about over-cooling, 7 % of the infant and the telling unitology group were over-cooled compared to 6 % in the control group that were below that target temperature on transport team arrival. So even the passive cooling, it really did not lead to a problematic over-cooling. And for secondary outcome, there was no detectable difference.

in the composite outcome of early neurologic morbidity or mortality between the groups 57 % versus 49%. The conclusion are that telonyl unitology does reduce the time to go temperature among outborn infants treated with cooling and that their findings highlights the potential for telonyl unitology in improving the timely delivery of care to this particular vulnerable population. I think that we may say, what's the difference 3.4 versus 4.6, but

I want to highlight that this is a topic that is actively being studied by a lot of that's more than an hour, but it still remains within the six hour window. And I think that we may be tempted to think, especially as young trainees that like, as long as it's done within the first six hours, it's okay. But there's more and more data that is showing that maybe earlier initiation by one hour at a time may have incremental benefits. And so this is, this is something that I was talking to a friend of mine about regarding like.

The Incubator (01:05:06.557)

That's more than an hour. Yeah.

The Incubator (01:05:21.033)

for sure.

Ben Courchia MD (01:05:32.142)

could tell in unitology, be a little bit ahead of the curve when it comes to highlighting something that will be beneficial. Maybe we don't have the data yet to show that cooling at one hour versus four hours is a massive difference, but yet we're able to do it already because if you activate a console system using telehealth, you might be able to achieve that goal. I thought this was a very interesting, I think it's a very interesting paper. One of the reasons we're highlighting this topic at Delphi as well is because this is coming.

The Incubator (01:05:47.101)

Mm-hmm.

Ben Courchia MD (01:05:59.526)

And you're reading this and you're like, my God, like if I take a job somewhere, I might be on the hook for providing tele-unitology services to outlying hospitals. I don't know about you, Daphne. I've never done this before.

The Incubator (01:05:59.999)

Mm-hmm.

The Incubator (01:06:10.931)

Yeah, I mean, we did extensively at the University of Florida and actually, I mean, Mike Weiss has been doing telesarnuts for some time. And actually, I mean, I think specifically for this indication, I think it's really interesting. You know, we talk about this all the time in our state collaborative for referral centers and many of our listeners at referral centers.

The difference between phone and tele in this situation is the babies change over time, right? So within the hour to two hours to sometimes four hours that you get a baby, they may look different than when the other professional sent the baby. So, I mean, being able to evaluate that infant by video at that time, I think is very valuable because we talk about this all the time. What if you get a baby who now looks pretty good, but didn't look pretty good or

Ben Courchia MD (01:06:49.251)

Mm-hmm.

The Incubator (01:07:04.317)

looked pretty good and now doesn't look pretty good. How does that change what you might do for that infant? So, yeah.

Ben Courchia MD (01:07:10.21)

For sure. For sure. And I think that, like I was saying earlier, for me, I know that the tech is there. You can get very high resolution video, and it's not like you're going to be on... It's not going to be like FaceTiming your grandmother across the globe. Sometimes it feels like, my God, am I really going to have to make a medical decision based on a very pixelated, shoddy type of image that's shaking? No. The devices are there. They're stable. And I think it's important for us to start learning about them because...

The Incubator (01:07:16.243)

Yeah, easy.

Ben Courchia MD (01:07:38.69)

tomorrow your hospital might say, we're gonna provide that service to our outlying neighboring hospitals. then, yeah, so I think it's gonna be an interesting topic and it's definitely an interesting study to say the least.

The Incubator (01:07:52.573)

You had one more you wanted to run through?

Ben Courchia MD (01:07:55.532)

Let's do it. I'm not really going to run through, but I'm going to do it. It's an important paper. This is a paper that was published in the Journal of Pediatrics. It's called Norepinephrine versus Dopamine for Septic Shock in Neonates, a randomized control trial. I feel like we're bearing the lead. It was an important paper, and we're reviewing it at the end of the episode. But it will be available as a Journal Club short, so that's OK. The question is always the same. Which Vezopracer do we use?

The Incubator (01:08:08.381)

Love it.

Ben Courchia MD (01:08:21.198)

as a first line agent for septic shock and neonates. Sepsis is an important cause of admission to the NICU. We've talked about sepsis a lot today already just on this journal club alone. And it's a significant contributor to neonatal morbidity and mortality, especially in low and middle income countries. Septic shock in particular has been associated with a high case fatality rate of about 40 to 80%. Now the management of septic shock involves timely initiation of fluids and vasoactive support along with other supportive measures and antibiotics. However,

There's a lack of well-defined management protocol for fluid refractory septic shock and neonates. And the plausible reasons include unclear definition of hypotension and neonates. We always come back to that question. Complex pathophysiologic process, ensuing cardiovascular compromise and a lack of robust evidence. Now the recently published pediatric and adult survival sepsis guidelines prefer the use of norepinephrine over dopamine as the first line vasoactive agent for the management of septic shock based on evidence which favors norepinephrine.

in terms of reduced all-cause mortality and better cardiovascular profile in adults. However, several pharmacological factors support the use of norepinephrine over dopamine, specifically in neonates. And there are several reasons. The first one being that the pathophysiology of septic shock involving low systemic vascular resistance can be addressed adequately by a potent alpha-1 agonist, such as norepi. Second, dopamine exerts its action through the release of norepinephrine

from sympathetic nerve endings, and this might become a limiting factor in sick neonates with limited reserves. So if you're providing it yourself via medication, then you might be overcoming that. the metabolism and clearance of dopamine is dependent upon post-menstrual age and may cause drug accumulation in unstable preterm neonates.

Lastly, norepinephrine may reduce pulmonary vascular resistance and improve pulmonary hypertension, which is a common association in neonatal sepsis. So the authors conducted this study to determine the efficacy and the safety of norepinephrine compared to dopamine as an initial vasoactive agent. This was a double-blind parallel group randomized control trial conducted at a tertiary center in northern India for over a period of 18 months.

Ben Courchia MD (01:10:37.162)

All neonates, both term and preterm, with fluid refractory septic shock admitted to the NICU, were included in the study. Each neonate was enrolled only once. Term neonates were enrolled until day 28 of life and preterm neonates until 40 weeks post menstrual age. The definition of shock was adapted from the American College of Critical Care Medicine guidelines as the presence of hypotension defined by systolic blood pressure, diastolic blood pressure, or mean blood pressure at or below the third centile for gestational age.

along with any two of the following criteria, a decreased urine output of less than 0.5 ml per kilo per hour over the past 12 hours, cap refill of four seconds or greater, a lactate greater than five, metabolic acidosis with a basic success greater than five, or superior vena cava flow less than 40 ml per kilo per minute. Hypotension was assessed via invasive blood pressure monitoring through an umbilical peripheral arterial line.

fluid refractoriness was defined by the failure of reversal of shock after receipt of one or more fluid boluses of 10 ml per kilo over 10 minutes guided by the assessment of fluid status. The diagnosis of sepsis was based on either a positive blood culture or a positive sepsis screen or a compatible clinical course as judged by the treating physician having received antibiotics for at least five days.

They excluded babies with congenital anomalies, moderate to severe HIE in the first 72 hours of life, neonates already on inotropes, and shock in the first 24 hours of surgery, and failure to obtain consent. The primary outcome of the study was the incidence of shock reversal at 30 minutes after the initiation of the vasopressor support. Shock reversal was defined again using the American College of Critical Care Medicine guidelines as the correction of hypotension. Along with any two clinical endpoints, CAP refueled

two seconds or less, normal pulses with no difference in quality between peripheral and central porous and warm extremities. Secondary outcomes include changes in cerebral tissue oxygenation, need for further escalation of vasoactive treatment, time to reversal of shock, requirement of steroids, incidence of hyperglycemia, defined at a blood sugar level of 180 or higher, tachyarrhythmia, sinus tachycardia, need for duration of need.

Ben Courchia MD (01:12:47.694)

I'm sorry, need and duration of respiratory support and changes in acid-base parameters at baseline six hours, 24 hours after the diagnosis of shock, including pH, bicarb, bay success, and lactate. The participants were basically randomly assigned to either receive norepi or dopamine in a one-to-one ratio stratified to less than 35 weeks and 35 weeks of greater subgroups. And all study investigators and healthcare personnel except the study nurse were blinded to the intervention.

The dose of norepi that they were using was 1.5 ml per kilo of norepi at 1 milligram per ml, was diluted in 50 ml of 5 % dextrose, and was initiated at 0.4 ml an hour, which equals to 0.2 microgram per kilo per minute. The dopamine group basically was started at 10 micrograms per kilo per minute. Shock reversal was assessed at 15 and 30 minutes of initiation of vasopressor support. The neonates who did not achieve therapeutic endpoints were started on other vasopressor drugs

as per the decision of the clinical team. Crossover to the alternate arm was not permitted, except in infants refractory to multiple vasoactive agents. So very interesting study. Let's get into the results. 18 neonates were eligible and randomized into norepi, 41 babies, dopamine, 39 babies. The majority of neonates had late onset neonatal sepsis, 60 % in the norepi group, 64 % in the dopamine group.

The median age at enrollment was four days, which was comparable between the two groups. And among the enrolled neonates, 49 % had a culture positive sepsis. So still, a lot of them were sort of this culture negative sepsis. The most common isolate were gram negative organism, and the mean gestational age was 33.2 weeks in the norepi group and 33.2 weeks in the dopamine group. No difference there. In terms of the primary outcome, the proportion of neonates attaining reversal of shock by 30 minutes

of initiation of vasoactive support was similar between the group. 31.7 % in the Neuropi group, 46 % in the dopamine group with a p-value of 0.19. The requirement of additional vasoactive agents and steroids was similar in the two group. There was no difference in the proportion of neonates attaining shock reversal at any time point between the Neuropi and dopamine group, 48.8 % versus 53.9%. The time to shock reversal was also similar.

Ben Courchia MD (01:15:07.342)

One hour in the norepinephrine group, one hour in the dopamine group. While the incidence of hyperglycemia was similar in the two groups, neonates enrolled in the dopamine group had a higher incidence of tachycardia, 2.4 % in the norepinephrine group versus 15.4 % in the dopamine group.

Ben Courchia MD (01:15:29.26)

The proportions of neonates with IVH grade three to four, ROP, neck, were similar between the two groups. There was also no difference in all-cause mortality between the two groups. When they were looking at some of these more specific endpoints, cerebral tissue oxygenation saturation were similar at 30 minutes and at six hours post-initiation of therapy, but they were significantly lower at 24 hours in the dopamine group. It's a very interesting finding. And in addition, neonates in the dopamine group were significantly more acidotic.

at 24 hours following initiation of vasoactive support with a pH of 7.27 in the norapy group compared to 7.19 in the dopamine group with a p-value of 0.04. The blood lactate levels were comparable between the group. In the subgroup analysis, looking at the different gestational age, they found no significant difference in the results in the less than 35-week subgroup. The dopamine group had significantly higher incidence of hyperglycemia compared

to the group that had, compared to the group that was a little bit more mature. I think that what's important here to note is that when we're looking at the number of babies, the number of infants less than 35 weeks was like 25 and 24, and above 35 weeks, 16 and 15. So actually, most of them were in that premature group.

The mean gestational age though was 33 weeks as we mentioned. So they were not that premature either. The conclusion of the article is that norepi and dopamine have comparable efficacy in neonates with fluid refractory septic shock. However, the dopamine group had higher incidence of tachycardia, lower pH and lower cerebral tissue oxygenation at 24 hours following the initiation of therapy. There is a need for larger multi-center trials evaluating the efficacy of different vasoactive agent in neonates with septic shock emphasizing

emphasizing the long-term neurodemental consequences of those interventions. A very interesting paper for a very interesting population.

The Incubator (01:17:28.018)

I can't.

What do you think?

Ben Courchia MD (01:17:33.324)

I think that there's more and more data that norepinephrine has a place in our arsenal of vasopressors. think we use it not as often as we should. And I think that when specifically the biggest problem I believe in our field is that we have a very difficult time in identifying the different types of shock. I think we're all very familiar with what the different types of shock look like, but in the adult world, it is a little bit more clear cut what you're dealing with. Are you dealing with

hypovolemic shock, are you dealing with septic shock, cardiogenic shock? In neonates, it sometimes feels like you're dealing with all of them at once. And it's not exactly clear then what should we go with. And so sometimes, yeah, the reflex of going dopamine first is because I'm not exactly sure what this is about. this baby, right, a baby that is having a bad IVH and is losing like, and is pooling some blood in the brain.

Is that hypovolemic shock? Like, is that enough blood that's being lost on a 600 gram baby to actually constitute hypovolemia? Or is the baby having an IVH because they are septic and then this is septic shock? I think that is where our field has always sort of had difficulties, not to the fault of the clinicians, but to the fault of the pathophysiology of our babies that is so sort of interlocked and complex with so many things happening at once. So I think that if you have fairly certain...

perspective that this is probably a fluid refractory septic shock, consider an ORP and you would be supported by some pretty robust evidence here.

The Incubator (01:18:56.319)

Hmm.

The Incubator (01:19:05.919)

I had two papers I wanted to highlight, but we are like way over time already. What do you think?

Ben Courchia MD (01:19:11.522)

Are you going to save them for next time?

The Incubator (01:19:14.803)

I mean, I guess I can save them for next time. How about I just do one? Okay, all right. It's a meta-analysis. So I'm not gonna go over the whole thing, but I will review the findings in the abstract so that people can go take a look. It's entitled All Cause Mortality and Infection-Related Outcomes of Hospital-Initiated Kangaroo Care versus Conventional Neonatal Care for Low Birth Weight Infants, a Systemic Review in Meta-Analysis.

Ben Courchia MD (01:19:15.532)

Or you want to do a quick one? Or you want to do one? Let's do it.

The Incubator (01:19:45.305)

and the lead author, Chiara Manati, senior author, Julia Bialicki. And this is in the Lancet Child and Adolescent Health, actually. So they wanted to evaluate specifically how kangaroo care might impact infection concerns for low birth weight infants. And again, there's a lot of data. I'm not gonna belabor the point, but I do think

They have a really nice background there, a reminder that most guidelines recommend one hour of uninterrupted kangaroo care a day. And the WHO actually recommends targeted durations of eight to 24 hours of kangaroo care per day when possible. So most of us, especially in the States, are kind of missing the mark on that. They eventually, in their data set, included 29 studies.

I will highlight, this is an argument everybody says, mainly from lower middle income countries. There are two papers from the US and one from the UK included. Some of the papers are quite old, one to two decades old, but they were included. And most of the studies were considered to be moderate to high quality. So I will just review some of these findings.

86 % of the studies reported all-cause mortality in the meta-analysis. And again, hospital-initiated. So all of these were done in a healthcare facility. I think some people hear low to middle-income countries and they think, we're just doing it anywhere willy-nilly. But these were in hospitals. So hospital-initiated kangaroo care reduced all-cause mortality, a pooled odds ratio of 0.77.

felt to be high quality evidence. 17 or 60 % of the trials reported sepsis as an outcome, and the pooled results show that kangaroo care reduced the odds of sepsis and odds ratio of 0.55, moderate quality evidence. Similarly, among the 11 or 38 % of studies reported invasive infection, the pooled results show that kangaroo care reduced the odds of invasive infection and odds ratio of 0.49, moderate quality evidence.

The Incubator (01:22:07.145)

Kangaroo care was associated with a significant reduction in the odds of sepsis-related or invasive infection-related mortality with an odds ratio of .63, high quality evidence. Was also associated with a reduction in hypothermia and odds ratio of .28, moderate quality of evidence, and a reduction in apnea, .46, moderate quality evidence.

And the meta-aggression showed this between study heterogeneity was most likely due to a variation in the level of kangaroo care offered as part of the conventional neonatal care. So some people as conventional care had a lot of kangaroo care and that was part of what was found. So I think the argument some people might say about this is, yeah, it's reducing infection in low to middle income countries.

I think potentially can do the same thing for us if we were as invested as some of these other countries were in prolonged gang root care. So I just wanted to highlight that paper before we log off today.

Ben Courchia MD (01:23:09.998)

Yeah, that's a very interesting point where the intervention has the proof is in the pudding. It's just like we're still not implementing as best as we can. And resources are not the issue. You're not missing a machine that your hospital can either afford. That's what's so frustrating, I think.

The Incubator (01:23:23.113)

Right?

The Incubator (01:23:26.567)

Yeah. Yeah. I mean, I think for us, the resource is the parent, right? So our system makes it so that we can't afford to bring parents to the bedside. But if you have a parent at bedside, then they should be given the option to do kangaroo care.

Ben Courchia MD (01:23:31.053)

Yeah.

Ben Courchia MD (01:23:42.316)

Yeah, and pretty interesting data on the infections as well. Anyway, thank you, Daphna, for running through this and for another episode of Journal Club. We will see you guys later this week with more incubator content. And again, feel free to leave a review or a five-star review on Apple Podcast. This helps us a lot. You guys have a good rest of your day.

The Incubator (01:24:02.367)

Thank you.

Bye everyone.